The fact that the effects of endogenous opioid peptides, such as the enkephalins, and exogenous opiates such as morphine, are mediated by at least three different types [mu (.mu.), delta (.delta.), kappa (K)] of opioid receptors raises the possibility that highly selective exogenous opioid agonists or antagonists might be developed. See W. R. Martin, Pharmacol. Rev., 35, 283 (1983). In fact, in recent years, some progress has been made in the development of selective opioid antagonists. Pentapeptides structurally related to the enkephalins have been reported to be highly delta-selective opioid antagonists. Such compounds (e.g., ICI 174864) currently are employed as pharmacologic probes of receptor function and structure, but they possess the disadvantage of low potency and poor penetration into the central nervous system (CNS). See J. W. Shaw et al., Life Sci., 31, 1259 (1982) and R. Cotton et al., Eur. J. Pharmacol., 97, 331 (1984). Portoghese et al. (U.S. Pat. No. 4,816,586) disclose certain opiate analogs which possess high selectivity and potency at delta receptors, including naltrindole (NTI) and 7-benzylidene-naltrexone (BNTX). Certain of these compounds have been reported both to deter ethanol ingestion in an alcohol-preferring rat line and to block morphine tolerance and dependence in the rat model. See, J. C. Froehlich et al., Alcoholism Clin. and Exp. Les., Abstract 20, page 315 (1991) and M. Sofuoglu et al., J. Pharmacol. Exp. Ther., 257, 676 (1991).
In recent years, it has also been shown that endogenous opioid peptides and exogenous opiates modulate immune responses both in vitro and in vivo. The enkephalins, for example, have been shown to enhance the expression of CD2 molecules on T lymphocytes both in normal individuals and immunosuppressed patients. See, for example, J. Wybran et al., J. Immunol., 123, 1068 (1979) and R. E. Faith et al., NIDA Res. Monogr., 54, 300 (1984). Enkephalins also can enhance murine host resistance to viral and tumor challenge and to anaphylactic shock as reported by R. E. Faith et al., Ann. N.Y. Acad. Sci., 496, 137 (1987). In other studies, the effects of enkephalins on immune function have been reported to be biphasic, with higher concentrations being suppressive and lower concentrations stimulatory. For example, see D. Maric et al., Ann. N.Y. Acad. Sci., 496, 126 (1987) and D. R. Oleson et al., Brain, Behavior and Immun., 2, 171 (1988).
Experiments to date that have examined the type of receptor on immune cells through which enkephalins exert such modulatory actions have suggested that it is an opioid receptor, similar to those found in the brain. In particular, it has been postulated that the enkephalin-binding receptor on cells of the immune system is of the delta subclass of opioid receptors. Thus, many of the effects of enkephalins on immune function can be blocked not only by the classical opioid receptor antagonist, naloxone, but also by the delta receptor-specific antagonist, ICI 174864. See, B. D. Jankovic et al., Ann. N.Y. Acad. Sci., 540, 691 (1988) and R. Cotton et al., Eur. J. Pharmacol., 97, 331 (1984).
NTI itself has been shown to be immunosuppressive and non-toxic both in vivo and in vitro. For example, K. Arakawa et al., in Transplant, 53, 951 (1992) and Transpl. Proc., 24, 696 (1992) have reported using NTI to prolong allograft survival in a rat renal transplant model and to suppress in vitro allogeneic and xenogeneic mixed lymphocyte responses. In both in vitro responses, NTI was found to be less effective than cyclosporine A (CsA), the current treatment of choice for allograft survival.
The autologous mixed lymphocyte response (AMLR) is the in vitro phenomenon of T cell proliferation in response to autologous class II (Ia/DR) antigen-bearing cells (B cells, macrophages, dendritic cells or activated T cells), and thus represents a type of autoimmune reaction. The AMLR was originally characterized in mice and, subsequently, was detected in humans. The cells that proliferate in the AMLR have been shown to be capable of immunomodulation by W. E. Crowe et al., Arth. Rheum., 28, 537 (1985).
It is generally believed that the AMLR can provide an in vitro model for studying immunoregulatory phenomena. For example, see, M. M. Kuntz et al., J. Exp. Med., 143, 1042 (1976); M. E. Weksler et al., J. Exp. Med., 146, 1833 (1977) and J. S. Smolen et al., J. Clin. Invest., 68, 1601 (1981). The viability of such a model is supported by the fact that the AMLR is frequently suppressed in autoimmune diseases, as well as in other diseases arising from disorders of immunoregulation, such as infectious mononucleosis, which is caused by Epstein-Barr virus. See, for example, R. L. Hirsch, Clin. Exp. Immunol., 64, 107 (1986). It has been suggested by W. E. Crowe et al., Arth. Rheum., 28, 537 (1985), that this association of suppressed AMLR with autoimmune disease indicates that the impaired immunoregulation manifest in the abnormal AMLR may be related to the pathogenesis of these disorders. In their studies of the use of NTI as an immunosuppressant, H. Nagase et al. (EPO 456833) reported that NTI strongly suppresses the MLR in preparations of allogeneic murine spleen cells. Therefore, a need exists for agents which can modulate the AMLR and immunoregulatory disorders associated therewith.